Method and apparatus for loading a benefical agent into an expandable medical device

ABSTRACT

The present invention relates to method and apparatus for dispensing a beneficial agent into an expandable medical device. The method includes the step of placing an expandable medical device on a mandrel, the medical device forming a cylindrical device having a plurality of openings and dispensing a beneficial agent into the plurality of openings.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication Ser. No. 60/412,489, filed on Sep. 20, 2002, which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates to a method and apparatus for loading abeneficial agent, such as a drug into an expandable medical device, andmore particularly, the invention relates to a method and apparatus fordispensing a beneficial agent into an expandable medical device such asa stent.

DESCRIPTION OF THE RELATED ART

[0003] Implantable medical devices are often used for delivery of abeneficial agent, such as a drug, to an organ or tissue in the body at acontrolled delivery rate over an extended period of time. These devicesmay deliver agents to a wide variety of bodily systems to provide a widevariety of treatments.

[0004] One of the many implantable medical devices which have been usedfor local delivery of beneficial agents is the coronary stent. Coronarystents are typically introduced percutaneously, and transportedtransluminally until positioned at a desired location. These devices arethen expanded either mechanically, such as by the expansion of a mandrelor balloon positioned inside the device, or expand themselves byreleasing stored energy upon actuation within the body. Once expandedwithin the lumen, these devices, called stents, become encapsulatedwithin the body tissue and remain a permanent implant.

[0005] Known stent designs include monofilament wire coil stents (U.S.Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and4,776,337); and, most prominently, thin-walled metal cylinders withaxial slots formed around the circumference (U.S. Pat. Nos. 4,733,665;4,739,762; and 4,776,337). Known construction materials for use instents include polymers, organic fabrics and biocompatible metals, suchas stainless steel, gold, silver, tantalum, titanium, and shape memoryalloys, such as Nitinol.

[0006] Of the many problems that may be addressed through stent-basedlocal delivery of beneficial agents, one of the most important isrestenosis. Restenosis is a major complication that can arise followingvascular interventions such as angioplasty and the implantation ofstents. Simply defined, restenosis is a wound healing process thatreduces the vessel lumen diameter by extracellular matrix deposition,neointimal hyperplasia, and vascular smooth muscle cell proliferation,and which may ultimately result in renarrowing or even reocclusion ofthe lumen. Despite the introduction of improved surgical techniques,devices, and pharmaceutical agents, the overall restenosis rate is stillreported in the range of 25 % to 50% within six to twelve months afteran angioplasty procedure. To treat this condition, additionalrevascularization procedures are frequently required, thereby increasingtrauma and risk to the patient.

[0007] One of the techniques under development to address the problem ofrestenosis is the use of surface coatings of various beneficial agentson stents. U.S. Pat. No. 5,716,981, for example, discloses a stent thatis surface-coated with a composition comprising a polymer carrier andpaclitaxel (a well-known compound that is commonly used in the treatmentof cancerous tumors). The patent offers detailed descriptions of methodsfor coating stent surfaces, such as spraying and dipping, as well as thedesired character of the coating itself: it should “coat the stentsmoothly and evenly” and “provide a uniform, predictable, prolongedrelease of the anti-angiogenic factor.” Surface coatings, however, canprovide little actual control over the release kinetics of beneficialagents. These coatings are necessarily very thin, typically 5 to 8microns deep. The surface area of the stent, by comparison is verylarge, so that the entire volume of the beneficial agent has a veryshort diffusion path to discharge into the surrounding tissue.

[0008] Increasing the thickness of the surface coating has thebeneficial effects of improving drug release kinetics including theability to control drug release and to allow increased drug loading.However, the increased coating thickness results in increased overallthickness of the stent wall. This is undesirable for a number ofreasons, including increased trauma to the vessel wall duringimplantation, reduced flow cross-section of the lumen afterimplantation, and increased vulnerability of the coating to mechanicalfailure or damage during expansion and implantation. Coating thicknessis one of several factors that affect the release kinetics of thebeneficial agent, and limitations on thickness thereby limit the rangeof release rates, duration of drug delivery, and the like that can beachieved.

[0009] In addition to sub-optimal release profiles, there are furtherproblems with surface coated stents. The fixed matrix polymer carriersfrequently used in the device coatings typically retain approximately30% of the beneficial agent in the coating indefinitely. Since thesebeneficial agents are frequently highly cytotoxic, sub-acute and chronicproblems such as chronic inflammation, late thrombosis, and late orincomplete healing of the vessel wall may occur. Additionally, thecarrier polymers themselves are often highly inflammatory to the tissueof the vessel wall. On the other hand, use of biodegradable polymercarriers on stent surfaces can result in the creation of “virtualspaces” or voids between the stent and tissue of the vessel wall afterthe polymer carrier has degraded, which permits differential motionbetween the stent and adjacent tissue. Resulting problems includemicro-abrasion and inflammation, stent drift, and failure tore-endothelialize the vessel wall.

[0010] Another significant problem is that expansion of the stent maystress the overlying polymeric coating causing the coating toplastically deform or even to rupture, which may therefore effect drugrelease kinetics or have other untoward effects. Further, expansion ofsuch a coated stent in an atherosclerotic blood vessel will placecircumferential shear forces on the polymeric coating, which may causethe coating to separate from the underlying stent surface. Suchseparation may again have untoward effects including embolization ofcoating fragments causing vascular obstruction.

[0011] In addition, it is not currently possible to deliver some drugswith a surface coating due to sensitivity of the drugs to water, othercompounds, or conditions in the body which degrade the drugs. Forexample, some drugs lose substantially all their activity when exposedto water for a period of time. When the desired treatment time issubstantially longer than the half life of the drug in water, the drugcannot be delivered by known coatings. Other drugs, such as protein orpeptide based therapeutic agents, lose activity when exposed to enzymes,pH changes, or other environmental conditions. These drugs which aresensitive to compounds or conditions in the body often cannot bedelivered using surface coatings.

[0012] Accordingly, it would be desirable to provide an apparatus andmethod for loading a beneficial agent into an expandable medical device,such as a stent, for delivery of agents, such as drugs, to a patient.

SUMMARY OF THE INVENTION

[0013] The present invention relates to an apparatus and method forloading a beneficial agent in an expandable medical device.

[0014] In accordance with one aspect of the invention, a method fordispensing a beneficial agent into an expandable medical device includesthe steps of placing an expandable medical device on a mandrel, themedical device forming a cylindrical device having a plurality ofopenings; and dispensing a beneficial agent into at least a portion ofthe plurality of openings.

[0015] In accordance with another aspect of the invention, a method forloading a beneficial agent in an expandable medical device includes thesteps of dispensing a beneficial agent through a dispenser into a firstopening in an expandable medical device; providing relative movementbetween the dispenser and the expandable medical device such that thedispenser is moved from alignment with the first opening in theexpandable medical device to alignment with a second opening in theexpandable medical device; and dispensing the beneficial agent into thesecond opening in the expandable medical device.

[0016] In accordance with a further aspect of the invention, anapparatus for loading a beneficial agent in an expandable medical deviceincludes a mandrel; an expandable medical device having a plurality ofopenings, the expandable medical device mounted on the mandrel; and adispenser configured to dispense a beneficial agent into the pluralityof openings in the expandable medical device.

[0017] In accordance with a further aspect of the invention, a methodfor loading a stent with a beneficial agent includes the steps ofproviding a stent with a plurality of holes; and dispensing a beneficialagent through a piezo-electric micro-jet into the plurality of holes.

[0018] In accordance with an additional aspect of the invention, anapparatus for loading a beneficial agent in a medical device comprises adispenser configured to dispense a beneficial agent into the pluralityof openings in the medical device; an observation system configured tolocate and identify the plurality of openings; and a central processingunit for controlling the dispensing of the beneficial agent into theopenings of the medical device, wherein an amount and location ofdroplets of beneficial agent dispensed into each of the openings in themedical device is determined by the central processing unit basedinformation obtained from the observation system.

[0019] In accordance with another aspect of the invention, a system forcontrolling a delivery of a beneficial agent into a plurality ofopenings of a medical device includes an observation system for mappinga medical device to obtain an actual position of a plurality of openingsof the medical device; a central processing unit for comparing theactual position of the plurality of openings of the medical device to ananticipated position from a manufacturing specification; and a dispenserfor dispensing a fluid beneficial agent into the plurality of openings.

[0020] In accordance with a further aspect of the invention, a systemfor controlling a delivery of a beneficial agent into an openingincludes a mandrel having a plurality of expandable medical devices; adispenser configured to dispense a first layer and a second layer of abeneficial agent into a plurality of openings in the expandable medicaldevice; and a central processing unit for controlling the dispensing ofthe beneficial agent into the openings of the expandable medical device.

[0021] In accordance with another aspect of the invention, a method ofremoving stents from a mandrel includes the steps of radially expandingthe stents by injecting air into at least a portion of the mandrel toinflate the mandrel and expand the stents; deflating the mandrel; andsliding the expanded stents off the mandrel.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0022] The invention will now be described in greater detail withreference to the preferred embodiments illustrated in the accompanyingdrawings, in which like elements bear like reference numerals, andwherein:

[0023]FIG. 1 is a perspective view of a therapeutic agent deliverydevice in the form of an expandable stent.

[0024]FIG. 2 is a cross-sectional view of a portion of a therapeuticagent delivery device having a beneficial agent contained in an openingin layers.

[0025]FIG. 3 is a cross-sectional view of a piezoelectric micro-jettingdispenser for delivery of a beneficial agent.

[0026]FIG. 4 is a cross-sectional view of a piezoelectric micro-jettingdispenser and an expandable medical device on a mandrel.

[0027]FIG. 5 is a perspective view of a system for loading an expandablemedical device with a beneficial agent.

[0028]FIG. 6 is a perspective view of a bearing for use with the systemof FIG. 5.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention relates to a method and apparatus forloading a beneficial agent into an expandable medical device. Moreparticularly, the invention relates to a method and apparatus forloading a beneficial agent in a stent.

[0030] First, the following terms, as used herein, shall have thefollowing meanings:

[0031] The term “beneficial agent” as used herein is intended to haveits broadest possible interpretation and is used to include anytherapeutic agent or drug, as well as inactive agents such as barrierlayers, carrier layers, therapeutic layers or protective layers.

[0032] The terms “drug” and “therapeutic agent” are used interchangeablyto refer to any therapeutically active substance that is delivered to abodily conduit of a living being to produce a desired, usuallybeneficial, effect. The present invention is particularly well suitedfor the delivery of antineoplastic, angiogenic factors,immuno-suppressants, anti-inflammatories and antiproliferatives(anti-restenosis agents) such as paclitaxel and Rapamycin for example,and antithrombins such as heparin, for example.

[0033] The term “matrix” or “biocompatible matrix” are usedinterchangeably to refer to a medium or material that, upon implantationin a subject, does not elicit a detrimental response sufficient toresult in the rejection of the matrix. The matrix typically does notprovide any therapeutic responses itself, though the matrix may containor surround a therapeutic agent, a therapeutic agent, an activatingagent or a deactivating agent, as defined herein. A matrix is also amedium that may simply provide support, structural integrity orstructural barriers. The matrix may be polymeric, non-polymeric,hydrophobic, hydrophilic, lipophilic, amphiphilic, and the like.

[0034] The term “bioresorbable” refers to a matrix, as defined herein,that can be broken down by either chemical or physical process, uponinteraction with a physiological environment. The bioresorbable matrixis broken into components that are metabolizable or excretable, over aperiod of time from minutes to years, preferably less than one year,while maintaining any requisite structural integrity in that same timeperiod.

[0035] The term “polymer” refers to molecules formed from the chemicalunion of two or more repeating units, called monomers. Accordingly,included within the term “polymer” may be, for example, dimers, trimersand oligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000.

[0036] The term “openings” refers to holes of any shape and includesboth through-openings and recesses.

[0037] Implantable Medical Devices with Holes

[0038]FIG. 1 illustrates a medical device 10 according to the presentinvention in the form of a stent design with large, non-deforming struts12 and links 14, which can contain openings (or holes) 20 withoutcompromising the mechanical properties of the struts or links, or thedevice as a whole. The non-deforming struts 12 and links 14 may beachieved by the use of ductile hinges which are described in detail inU.S. Pat. No. 6,241,762 which is incorporated hereby by reference in itsentirety. The holes 20 serve as large, protected reservoirs fordelivering various beneficial agents to the device implantation site.

[0039] As shown in FIG. 1, the openings 20 can be circular 22,rectangular 24, or D-shaped 26 in nature and form cylindrical,rectangular, or D-shaped holes extending through the width of themedical device 10. It can be appreciated that the openings 20 can beother shapes without departing from the present invention.

[0040] The volume of beneficial agent that can be delivered usingopenings 20 is about 3 to 10 times greater than the volume of a 5 microncoating covering a stent with the same stent/vessel wall coverage ratio.This much larger beneficial agent capacity provides several advantages.The larger capacity can be used to deliver multi-drug combinations, eachwith independent release profiles, for improved efficacy. Also, largercapacity can be used to provide larger quantities of less aggressivedrugs and to achieve clinical efficacy without the undesirableside-effects of more potent drugs, such as retarded healing of theendothelial layer.

[0041]FIG. 2 shows a cross-section of a medical device 10 in which oneor more beneficial agents have been loaded into the opening 20 inlayers. Examples of some methods of creating such layers andarrangements of layers are described in U.S. patent application Ser. No.09/948,989, filed on Sep. 7, 2001, which is incorporated herein byreference in its entirety. Although the layers are illustrated asdiscrete layers, the layers can also mix together upon delivery toresult in an inlay of beneficial agent with concentration gradients oftherapeutic agents but without distinct boundaries between layers.

[0042] According to one example, the total depth of the opening 20 isabout 100 to about 140 microns, typically 125 microns and the typicallayer thickness would be about 2 to about 50 microns, preferably about12 microns. Each typical layer is thus individually about twice as thickas the typical coating applied to surface-coated stents. There would beat least two and preferably about ten to twelve such layers in a typicalopening, with a total beneficial agent thickness about 25 to 28 timesgreater than a typical surface coating. According to one preferredembodiment of the present invention, each of the openings have an areaof at least 5×10⁻⁶ square inches, and preferably at least 7×10⁻⁶ squareinches. Typically, the openings are filled about 50% to about 75% fullof beneficial agent.

[0043] Since each layer is created independently, individual chemicalcompositions and pharmacokinetic properties can be imparted to eachlayer. Numerous useful arrangements of such layers can be formed, someof which will be described below. Each of the layers may include one ormore agents in the same or different proportions from layer to layer.The layers may be solid, porous, or filled with other drugs orexcipients. As mentioned above, although the layers are depositedseparately, they may mix forming an inlay without boundaries betweenlayers.

[0044] As shown in FIG. 2, the opening 20 is filled with a beneficialagent. The beneficial agent includes a barrier layer 40, a therapeuticlayer 30, and a cap layer 50.

[0045] Alternatively, different layers could be comprised of differenttherapeutic agents altogether, creating the ability to release differenttherapeutic agents at different points in time. The layers of beneficialagent provide the ability to tailor a delivery profile to differentapplications. This allows the medical device according to the presentinvention to be used for delivery of different beneficial agents to awide variety of locations in the body.

[0046] A protective layer in the form of a cap layer 50 is provided at atissue contacting surface of a medical device. The cap layer 50 canblock or retard biodegradation of subsequent layers and/or blocks orretards diffusion of the beneficial agent in that direction for a periodof time which allows the delivery of the medical device to a desiredlocation in the body. When the medical device 10 is a stent which isimplanted in a lumen, the barrier layer 40 is positioned on a side ofthe opening 20 facing the inside of the lumen. The barrier layer 40prevents the therapeutic agent 30 from passing into the lumen and beingcarried away without being delivered to the lumen tissue.

[0047] Typical formulations for therapeutic agents incorporated in thesemedical devices are well known to those skilled in the art.

[0048] Uses for Implantable Medical Devices

[0049] Although the present invention has been described with referenceto a medical device in the form of a stent, the medical devices of thepresent invention can also be medical devices of other shapes useful forsite-specific and time-release delivery of drugs to the body and otherorgans and tissues. The drugs may be delivered to the vasculatureincluding the coronary and peripheral vessels for a variety oftherapies, and to other lumens in the body. The drugs may increase lumendiameter, create occlusions, or deliver the drug for other reasons.

[0050] Medical devices and stents, as described herein, are useful forthe prevention of amelioration of restenosis, particularly afterpercutaneous transluminal coronary angioplasty and intraluminal stentplacement. In addition to the timed or sustained release ofanti-restenosis agents, other agents such as anti-inflammatory agentsmay be incorporated into the multi-layers incorporated in the pluralityof holes within the device. This allows for site-specific treatment orprevention any complications routinely associated with stent placementsthat are known to occur at very specific times after the placementoccurs.

[0051] Methods and Systems for Loading a Beneficial Agent in a MedicalDevice

[0052]FIG. 3 shows a piezoelectric micro-jetting dispenser 100 used todispense a beneficial agent into the opening of a medical device. Thedispenser 100 has a capillary tube 108 having a fluid outlet or orifice102, a fluid inlet 104, and an electrical cable 106. The piezoelectricdispenser 100 preferably includes a piezo crystal 110 within a housing112 for dispensing a fluid droplet through the orifice 102. The crystal110 surrounds a portion of the capillary tube 108 and receives anelectric charge that causes the crystal to vibrate. When the crystalvibrates inward, it forces a tiny amount of fluid out of the fluidoutlet 102 of the tube 108 to fill an opening 20 in a medical device. Inaddition, when the crystal vibrates outward, the crystal pullsadditional fluid into the tube 108 from a fluid reservoir connected tothe inlet 104 to replace the fluid that has been dispensed into theopening of the medical device.

[0053] In one embodiment as shown in FIG. 3, the micro-jetting dispenser100 includes an annular piezoelectric (PZT) actuator 110 bonded to aglass capillary 108. The glass capillary 108 is connected at one end toa fluid supply (not shown) and at the other end has an orifice 102generally in the range of about 0.5 to about 150 microns, and morepreferably about 30 to about 60 microns. When a voltage is applied tothe PZT actuator, the cross-section of the capillary glass 108 isreduced/increased producing pressure variations of the fluid enclosed inthe glass capillary 108. These pressure variations propagate in theglass capillary 108 toward the orifice 102. The sudden change incross-section (acoustic impedance) at the orifice 102, causes a dropletto be formed. This mode of producing droplets is generally called dropon demand (DOD).

[0054] In operation, the micro-jetting dispenser 100, depending on theviscosity and contact angle of the fluid, can require either positive ornegative pressure at the fluid inlet 104. Typically, there are two waysto provide pressure at the fluid inlet 104. First, the pressure at thefluid inlet 104 can be provided by either a positive or a negative headby positioning of the fluid supply reservoir. For example, if the fluidreservoir is mounted only a few millimeters above the dispenser 100, aconstant positive pressure will be provided. However, if the fluidreservoir is mounted a few millimeters below the dispenser 100, theorifice 102 will realize a negative pressure.

[0055] Alternatively, the pressure of the fluid at the inlet 104 can beregulated using existing compressed air or vacuum sources. For example,by inserting a pressure vacuum regulator between the fluid source andthe dispenser 100, the pressure can be adjusted to provide a constantpressure flow to the dispenser 100.

[0056] In addition, a wide range of fluids including beneficial agentscan be dispensed through the dispenser 100. The fluids preferably have aviscosity of no greater than about 40 centipoise. The droplet volume ofthe dispenser 100 is a function of the fluid, orifice 102 diameter, andactuator driving parameter (voltage and timing) and usually ranges fromabout 50 picoliters to about 200 picoliters per droplet. If a continuousdroplet generation is desired, the fluid can be pressurized and asinusoidal signal applied to the actuator to provide a continuousjetting of fluids. Depending on the beneficial agent dispensed, eachdroplet may appear more like a filament.

[0057] It can be appreciated that other fluid dispensing devices can beused without departing from the present invention. In one embodiment,the dispenser is a piezoelectric micro-jetting device manufactured byMicroFab Technologies, Inc., of Plano, Tex.

[0058] The electric cable 106 is preferably connected to associateddrive electronics (not shown) for providing a pulsed electric signal.The electric cable 106 provides the electric signal to control thedispensing of the fluid through the dispenser 100 by causing the crystalto vibrate.

[0059]FIG. 4 shows an expandable medical device in the form of a stent140 receiving a droplet 120 of a beneficial agent from a piezoelectricmicrojetting dispenser 100. The stent 140 is preferably mounted to amandrel 160. The stent 140 can be designed with large, non-deformingstruts and links (as shown in FIG. 1), which contain a plurality ofopenings 142 without compromising the mechanical properties of thestruts or links, or the device as a whole. The openings 142 serve aslarge, protected reservoirs for delivering various beneficial agents tothe device implantation site. The openings 142 can be circular,rectangular, or D-shaped in nature and form cylindrical, rectangular orD-shaped holes extending through the width of the stent 140. Inaddition, openings 142 having a depth less than the thickness of thestent 140 may also be used. It can be appreciated that other shapedholes 142 can be used without departing from the present invention.

[0060] The volume of the hole 142 will vary depending on the shape andsize of the hole 142. For example, a rectangular shaped opening 142having a width of 0.1520 mm (0.006 inches) and a height of 0.1270 mm(0.005 inches) will have a volume of about 2.22 nanoliters. Meanwhile, around opening having a radius of 0.0699 mm (0.00275 inches) will have avolume of about 1.87 nanoliters. A D-shaped opening having a width of0.1520 mm (0.006 inches) along the straight portion of the D, has avolume of about 2.68 nanoliters. The openings according to one exampleare about 0.1346 mm (0.0053 inches) in depth having a slight conicalshape due to laser cutting.

[0061] Although a tissue supporting device configuration has beenillustrated in FIG. 1, which includes ductile hinges, it should beunderstood that the beneficial agent may be contained in openings instents having a variety of designs including many of the known stents.

[0062] The mandrel 160 can include a wire member 162 encapsulated by anouter jacket 164 of a resilient or a rubber-like material. The wiremember 162 may be formed from a metallic thread or wire having acircular cross-section. The metallic thread or wire is preferablyselected from a group of metallic threads or wire, including Nitinol,stainless steel, tungsten, nickel, or other metals having similarcharacteristics and properties.

[0063] In one example, the wire member 162 has an outer diameter ofbetween about 0.889 mm (0.035 inches) and about 0.991 mm (0.039 inches)for use with a cylindrical or implantable tubular device having an outerdiameter of about 3 mm (0.118 inches) and an overall length of about 17mm (0.669 inches). It can be appreciated that the outer diameter of thewire member 162 will vary depending on the size and shape of theexpandable medical device 140.

[0064] Examples of rubber-like materials for the outer jacket 164include silicone, polymeric materials, such as polyethylene,polypropylene, polyvinyl chloride (PVC), ethyl vinyl acetate (EVA),polyurethane, polyamides, polyethylene terephthalate (PET), and theirmixtures and copolymers. However, it can be appreciated that othermaterials for the outer jacket 164 can be implemented, including thoserubber-like materials known to those skilled in the art.

[0065] In one embodiment, the wire member 162 is encapsulated in atubular outer jacket 164 having an inner diameter of about 0.635 mm(0.25 inches). The outer jacket 164 can be mounted over the wire member162 by inflating the tubular member to increase to a size greater thanthe outer diameter of the wire member 162. The tubular member can beinflated using an air pressure device known to those skilled in the art.The wire member 162 is placed inside of the outer jacket 164 by floatingthe outer jacket 164 of silicon over the wire member 162. However, itcan be appreciated that the wire member 162 can be encapsulated in anouter jacket of silicon or other rubber-like material by any methodknown to one skilled in the art.

[0066] In one embodiment for loading stents having a diameter of about 3mm (0.118 inches) and a length of about 17 mm (0.669 inches), a wiremember 162 having an outer diameter of 0.939 mm (0.037 inches) isselected. In one example, the wire member 162 is about 304.8 mm (12inches) in length. The outer jacket 164 has an inner diameter of about0.635 mm (0.025 inches).

[0067] The expandable medical device or stent 140 is then loaded ontothe mandrel 160 in any method known to one skilled in the art. In oneembodiment, the stents 140 and the mandrel 160 are dipped into a volumeof lubricant to lubricate the stents 140 and the mandrel 160. The stents140 are then loaded onto the mandrel 160. The drying of the stents 140and the mandrel 160 create a substantially firm fit of the stents 140onto the mandrel 160. Alternatively, or in addition to drying, thestents 140 can be crimped onto the mandrel by a method known to oneskilled in the art onto the mandrel 160. The crimping ensures that thestents 140 will not move or rotate during mapping or filling of theopenings.

[0068]FIG. 5 shows a system 200 for loading a beneficial agent in anexpandable medical device. The system 200 includes a dispenser 210 fordispensing a beneficial agent into an opening of an expandable medicaldevice, a reservoir of beneficial agent 218 at least one observationsystem 220, and a mandrel 230 having a plurality of expandable medicaldevices 232 attached to the mandrel 230. The system 200 also includes aplurality of bearings 240 for supporting the rotating mandrel 230, ameans for rotating and translating the mandrel 250 along a cylindricalaxis of the expandable medical device 232, a monitor 260, and a centralprocessing unit (CPU) 270.

[0069] The dispenser 210 is preferably a piezoelectric dispenser fordispensing a beneficial agent into the opening in the medical device232. The dispenser 210 has a fluid outlet or orifice 212, a fluid inlet214 and an electrical cable 216. The piezoelectric dispenser 200dispenses a fluid droplet through the orifice 212.

[0070] At least one observation system 220 is used to observe theformation of the droplets and the positioning of the dispenser 210relative to the plurality of openings in the medical device 232. Theobservation system 220 may include a charge coupled device (CCD) camera.In one embodiment, at least two CCD cameras are used for the fillingprocess. The first camera can be located above the micro-jettingdispenser 210 and observes the filling of the medical device 232. Thefirst camera is also used for mapping of the mandrel 230 as will bedescribed below. A second camera is preferably located on a side of themicro-jetting dispenser 210 and observes the microjetting dispenser 210from a side or orthogonal view. The second camera is preferably used tovisualize the micro-jetting dispenser during the positioning of thedispenser before loading of the medical device 232 with a beneficialagent. However, it can be appreciated that the observation system 220can include any number of visualization systems including a camera, amicroscope, a laser, machine vision system, or other known device to oneskilled in the art. For example, refraction of a light beam can be usedto count droplets from the dispenser. The total magnification to themonitor should be in the range of 50 to 100 times.

[0071] In one embodiment, a LED synchronized light 224 with the PZTpulse provides lighting for the system 200. The delay between the PZTpulse and the LED pulse is adjustable, allowing the capture of thedroplet formation at different stages of development. The observationsystem 220 is also used in mapping of the mandrel 230 and medicaldevices 232 for loading of the openings. In one embodiment, rather thanusing a LED synchronized light 224, the lighting is performed using adiffused flourescent lighting system. It can be appreciated that otherlighting systems can be used without departing from the presentinvention.

[0072] A plurality of expandable medical devices 232 are mounted to themandrel 230 as described above. For example, a mandrel which is about 12inches in length can accommodate about 11 stents having a length ofabout 17 mm each. Each mandrel 230 is labeled with a bar code 234 toensure that each mandrel is properly identified, mapped, and then filledto the desired specifications.

[0073] The mandrel 230 is positioned on a plurality of bearings 240. Asshown in FIG. 6, one example of the bearings 240 have a V-shaped notch242. The mandrel 230 is positioned within the V-shaped notch 242 andsecured using a clip 244. The clip 244 is preferably a coil spring,however, other means of securing the mandrel within the V-shaped notchcan be used including any type of clip or securing means can be used.The bearings 240 can be constructed of a metallic material, preferablydifferent than the mandrel wire, such as stainless steel, copper, brass,or iron.

[0074] The mandrel 230 is connected to a means for rotating andtranslating the mandrel 250 along the cylindrical axis of the medicaldevice 232. The means for rotating and translating the mandrel 250 canbe any type or combination of motors or other systems known to oneskilled in the art.

[0075] In one embodiment, the mandrel 250 and medical device 232 aremoved from a first position to a second position to fill the openings ofthe medical device 232 with the beneficial agent. In an alternativeembodiment, the system further includes a means for moving thedispensing system along the cylindrical axis of the medical device 232from a first position to a second position.

[0076] A monitor 260 is preferably used to observe the loading of themedical device 232 with a beneficial agent. It can be appreciated thatany type of monitor or other means of observing the mapping and loadingprocess can be used.

[0077] A central processing unit 270 (or CPU) controls the loading ofthe medical device 232 with the beneficial agent. The CPU 270 providesprocessing of information on the medical device 232 for the dispensingof the beneficial agent. The CPU 270 is initially programmed with themanufacturing specifications as to the size, shape and arrangement ofthe openings in the medical device 232. A keyboard 272 is preferablyused to assist with the loading of the CPU 270 and for input ofinformation relating to the loading process.

[0078] The medical devices 232 are preferably affixed to the mandrel 230and mapped prior to the loading process. The mapping process allows theobservation system and associated control system to determine a preciselocation of each of the openings which may vary slightly from device todevice and mandrel to mandrel due to inaccuracies of loading the deviceson the mandrels. This precise location of each of the openings is thensaved as the specific map for that specific mandrel. The mapping of themandrel 230 is performed by using the observation system to ascertainthe size, shape and arrangement of the openings of each medical device232 located on the mandrel 230. Once the mandrel 230 including theplurality of medical devices 232 have been mapped, the mapping resultsare compared to the manufacturing specifications to provide adjustmentsfor the dispenser to correctly dispense the beneficial agent into eachof the holes of the medical device 232.

[0079] In an alternative embodiment, the mapping of the mandrel 230 isperformed on an opening by opening comparison. In operation, theobservation system maps a first opening in the medical device andcompares the mapping result to the manufacturing specifications. If thefirst opening is positioned as specified by the manufacturingspecifications, no adjustment is needed. However, if the first openingis not positioned as specified by the manufacturing specifications, anadjustment is recorded and an adjustment is made during the dispensingprocess to correct for the position which is different than as specifiedin the manufacturing specifications. The mapping is repeated for eachopening of the medical device until each medical device 232 has beenmapped. In addition, in one embodiment, if an opening is mapped and theopening is positioned pursuant to the manufacturing specifications, themapping process can be designed to proceed to map at every other openingor to skip any number of openings without departing from the presentinvention.

[0080] After the mandrel has been mapped, the medical device 232 isfilled with the beneficial agent based on the manufacturers'specification and adjustments from the mapping results. The CPU providesthe programmed data for filling of each medical device 232. Theprogrammed data includes the medical device design code, date created,lot number being created, number of medical devices 232 on the mandrel,volume of each opening in the medical device 232, different beneficialagents to be loaded or dispensed into the openings in the medical device232, the number of layers, drying/baking time for each layer, and anyother data.

[0081] In one embodiment, the medical device 232 will have at least 10beneficial agent layers which will be filled including at least onebarrier layer, at least one therapeutic layer having a beneficial agent,and at least one cap layer. The beneficial agent layers may includelayers which vary in concentration and strength of each solution of drugor therapeutic agent, amount of polymer, and amount of solvent.

[0082] In operation, the operator will input or scan the bar code 234 ofthe mandrel into the CPU 270 before the filling process begins. Theinitial filling generally includes a mixture of polymer and solvent tocreate a barrier layer. Each of the openings are typically filled toabout 80% capacity and then the mandrel is removed from the system andplaced into an oven for baking. The baking process evaporates the liquidportion or solvent from the openings leaving a solid layer. The mandrelis typically baked for about 60 minutes plus or minus 5 minutes at about55 degrees C. To assist in error prevention, the CPU software receivesthe bar code of the mandrel and will not begin filling the second layeruntil at least 60 minutes since the last filling. The second layer andsubsequent layers are then filled in the same manner as the first layeruntil the opening has been filled to the desired capacity. The reservoir218 can also be bar coded to identify the solution in the reservoir.

[0083] The observation system 220 also can verify that the dispenser 210is dispensing the beneficial agent into the openings through eitherhuman observation on the monitor 270 or via data received from theobservation system and conveyed to the CPU to confirm the dispensing ofthe beneficial agent in the openings of the medical device 232.Alternatively, refraction of a light beam can be used to count dropletsdispensed at a high speed.

[0084] The dispensers 100 run very consistently for hours at a time, butwill drift from day to day. Also, any small change in the waveform willchange the drop size. Therefore, the output of the dispenser 100 can becalibrated by firing a known quantity of drops into a cup and thenmeasuring the amount of drug in the cup. Alternatively, the dispenser100 can be fired into a cup of known volume and the number of dropsrequired to exactly fill it can be counted.

[0085] In filling the openings of the medical device 232, themicro-jetting dispenser 100 dispenses a plurality of droplets into theopening. In one preferred embodiment, the dispenser is capable ofdispensing 3000 shots per second through a micro-jetting dispenser ofabout 40 microns. However, the droplets are preferably dispensed atbetween about 8 to 20 shots per hole depending on the amount of fillrequired. The micro-jetting dispenser fills each hole (or the holesdesired) by proceeding along the horizontal axis of the medical device232. The CPU 270 turns the dispenser 100 on and off to fill the openingssubstantially without dispensing liquid between openings on the medicaldevice. Once the dispenser has reached an end of the medical device 232,the means for rotating the mandrel rotates the mandrel and a secondpassing of the medical device 232 along the horizontal axis isperformed. In one embodiment, the medical devices 232 are stents havinga diameter of about 3 mm and a length of about 17 mm and can be filledin about six passes. Once the medical device 232 is filled, thedispenser 210 moves to the next medical device 232 which is filled inthe same manner.

[0086] The CPU 270 insures that the mandrel is filled accurately byhaving safety factors built into the filling process. It has also beenshown that by filling the openings utilizing a micro-jetting dispenser,the amount of drugs or therapeutic agent used is substantially less thancoating the medical device 232 using previously known method includingspraying or dipping. In addition, the micro-jetting of a beneficialagent provides an improved work environment by exposing the worker to asubstantially smaller quantity of drugs than by other known methods.

[0087] The system 200 also includes an electrical power source 290 whichprovides electricity to the piezoelectric micro-jetting dispenser 210.

[0088] The medical devices 232 can be removed from the mandrel byexpanding the devices and sliding them off the mandrel. In one example,stents can be removed from the mandrel by injecting a volume of airbetween the outer diameter of the wire member 162 and the inner diameterof the outer jacket. The air pressure causes the medical device 232 toexpand such that the inner diameter of the medical device 232 is greaterthan the outer diameter of the mandrel. In one embodiment, a die isplace around the mandrel to limit the expansion of the medical device232 as the air pressure between the outer diameter of the wire member162 and the inner diameter of the outer jacket 164. The die can beconstructed of stainless steel or plastics such that the medical devices232 are not damaged during removal from the mandrel. In addition, in apreferred embodiment, the medical devices 232 are removed four at a timefrom the mandrel. A 12-inch mandrel will accommodate about 11, 3 mm by17 mm medical devices having approximately 597 openings.

EXAMPLE 1

[0089] In the example below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning.

[0090] DMSO=Dimethyl Sulfoxide

[0091] IV=Inherent Viscosity

[0092] PLGA=poly(lactide-co-glycolide) TABLE I Solutions Drug PolymerSolvent A None 4% PLGA DMSO 50/50 IV = 0.82 DA 0.64% 8% PLGA DMSOpaclitaxel 50/50 IV = 0.59 DA 0.64% 8% PLGA DMSO paclitaxel 50/50 IV =0.60 DD 0.14% 8% PLGA DMSO paclitaxel 50/50 IV = 0.59 L None 8% PLGADMSO 50/50 IV = 0.59

[0093] TABLE II Layer No., Layer No. Solution this Solution 1 A 1 2 A 23 A 3 4 A 4 5 A 5 6 A 6 7 A 7 8 A 8 9 A 9 10 DA 1 11 DA 2 12 DD 1 13 L 1

[0094] A plurality of medical devices, preferably 11 medical devices permandrel are placed onto a series of mandrels. Each mandrel is bar codedwith a unique indicia which identifies at least the type of medicaldevice, the layers of beneficial agents to be loaded into the opening ofthe medical devices, and a specific identity for each mandrel. The barcode information and the mapping results are stored in the CPU forloading of the stent.

[0095] a first mixture of poly(latide-co-glycolide) (PLGA) (BirminghamPolymers, Inc.), and a suitable solvent, such as DMSO is prepared. Themixture is loaded by droplets into holes in the stent. The stent is thenpreferably baked at a temperature of 55 degrees C for about 60 minutesto evaporate the solvent to form a barrier layer. A second layer is laidover the first by the same method of filling polymer solution into theopening followed by solvent evaporation. The process is continued until9 individual layers have been loaded into the openings of the medicaldevice to form the barrier layer.

[0096] A second mixture of paclitaxel, PLGA, and a suitable solvent suchas DMSO forming a therapeutic layer is then introduced into the openingsof the medical device over the barrier layer. The solvent is evaporatedto form a drug filled protective layer and the filling and evaporationprocedure repeated until the hole is filled until the desired amount ofpaclitaxel has been added to the openings of the medical device.

[0097] A third mixture of PLGA and DMSO is then introduced into theopenings over the therapeutic agent to form a cap layer. The solvent isevaporated and the filling and evaporation procedure repeated until thecap layer has been added to the medical device, in this embodiment, asingle cap layer has been added.

[0098] In order to provide a plurality of layers of beneficial agentshaving a desired solution, the reservoir is replaced and thepiezoelectric microjetting dispenser is cleaned. The replacement of thereservoir and cleaning of the dispenser insures that the differentbeneficial layers have a desired solution including the correct amountof drugs, solvent, and polymer.

[0099] Following implantation of the filled medical device in vivo, thePLGA polymer degrades via hydrolysis and the paclitaxel is released.

[0100] While the invention has been described in detail with referenceto the preferred embodiments thereof, it will be apparent to one skilledin the art that various changes and modifications can be made andequivalents employed, without departing from the present invention.

1-76. (cancelled).
 77. A method for ensuring accurate dispensing of abeneficial agent into an implantable medical device, the methodcomprising: placing an implantable medical device having a plurality ofopenings on a movable support; dispensing a beneficial agent into theplurality of openings with a dropwise dispensing device; recording thedispensing process during dispensing with an observation systemincluding at least one camera; and verifying that the openings have beenfilled with the observation system.
 78. The method of claim 77, furthercomprising dispensing the beneficial agent with a piezoelectricmicro-jetting dispenser.
 79. The method of claim 77, wherein theplurality of openings have different volumes and the amount ofbeneficial agent dispensed is adjusted based on the size of the opening.80. The method of claim 77, further comprising adjusting an amount ofthe beneficial agent dispensed into an opening based on an amount ofbeneficial agent previously dispensed into the opening.
 81. The methodof claim 77, wherein the implantable medical device is a stent.
 82. Themethod of claim 77, wherein the movable support is a mandrel having aresilient outer surface which seals a bottom side of the openings. 83.The method of claim 77, wherein the beneficial agent comprises a drug.84. A method for ensuring accurate dispensing of a beneficial agent intoan implantable medical device, the method comprising: placing animplantable medical device having a plurality of openings on a movablesupport; providing a central processing unit connected to a motionsystem for the movable support and a dispensing system; delivering tothe central processing unit a manufacturing specification for theimplantable medical device including the size, shape, and arrangement ofthe openings; mapping the implantable medical device on the movablesupport to obtain an actual specification of the medical deviceincluding locations of the openings; combining the manufacturingspecification and a plurality of coordinates from the mapping of theimplantable medical device to form a specific map of the implantablemedical device which is stored in the central processing unit; anddispensing a beneficial agent into the plurality of openings inaccordance with the specific map.
 85. The method of claim 84, furthercomprising verifying that the openings have been filled with theobservation system.
 86. The method of claim 84, wherein the mapping isperformed by a camera.
 87. The method of claim 84, wherein the mappingis performed by a machine vision system.
 88. The method of claim 84,further comprising an observation system for observing the dispensing ofthe beneficial agent into the plurality of openings.
 89. The method ofclaim 84, further comprising verifying the dispensing of the beneficialagent into the plurality of opening of the medical device.
 90. Anapparatus for ensuring accurate dispensing of a beneficial agent in animplantable medical device, the apparatus comprising: a movable supportconfigured to receive the implantable medical device having openings; amotion system for moving the movable support; a camera for creatingimages of the implantable medical device; a central processing unitconnected to the motion system creating a specific map of theimplantable medical device, wherein the central processing unit isprovided with a manufacturing specification for the implantable medicaldevice including the size, shape, and arrangement of the openings, thecentral processing unit controls the camera to map the implantablemedical device on the movable support to obtain an actual location ofthe openings in the implantable medical device, and the centralprocessing unit combines the manufacturing specification and actuallocation of the openings determined by mapping of the implantablemedical device to create a specific map of the implantable medicaldevice which is stored in the central processing unit; and a dispenserconfigured to dispense a beneficial agent into the openings in theimplantable medical device in a dropwise manner based on the specificmap of the implantable medical device created by the central processingunit.
 91. The apparatus of claim 90, wherein the central processing unitcontrols the dispensing of the beneficial agent into the openings of theimplantable medical device with the dispenser.
 92. The apparatus ofclaim 90, further comprising an observation system for verifyingdispensing of the beneficial agent into the openings in the implantablemedical device.
 93. The apparatus of claim 92, wherein the observationsystem includes a monitor for observing the dispensing of the beneficialagent into the plurality of openings of the expandable medical device.94. The apparatus of claim 90, wherein the movable support is a mandrel.95. The apparatus of claim 94, wherein the mandrel is encapsulated witha rubber-like material.
 96. The apparatus of claim 90, wherein thedispenser is a piezoelectric micro-jetting dispenser.
 97. The apparatusof claim 14, wherein the implantable medical device is a stent.